Regional cholinergic denervation of cortical microvessels and nitric oxidesynthase-containing neurons in Alzheimer's disease

In the present study, we investigated in the human cerebral cortex whether, as in the rat, basal forebrain cholinergic neurons innervate cortical micr ovessels and nitric oxide synthase-containing neurons and, further, we comp ared the status of this innervation between aged controls and neuropatholog ically confirmed cases of Alzheimer's disease. Using immunocytochemistry of choline acetyltransferase coupled to reduced nicotinamide adenine dinucleo tide phosphate-diaphorase histochemistry, we show in young human subjects t he presence of a cholinergic input to the cortical microcirculation, and of numerous perisomatic and peridendritic contacts between cholinergic nerve terminals and reduced nicotinamide adenine dinucleotide phosphate-diaphoras e neurons. A regional cholinergic denervation of both cortical microvessels and reduced nicotinamide adenine dinucleotide phosphate-diaphorase neurons was found in Alzheimer's disease patients as compared to aged controls, an d it paralleled the loss of total cholinergic nerve terminals in the corres ponding areas of the cerebral cortex. The vascular denervation was more sev ere in the temporal (77%, P < 0.05) than in the frontal (48%, not significa nt) cortex, and the reduced nicotinamide adenine dinucleotide phosphate-dia phorase intracortical neurons were similarly deprived of their cholinergic input (P < 0.01) in both regions. Interestingly, a significant increase in luminal diameter (48%, P < 0.01) and area ( > 160%, P < 0.01) of perfused m icrovessels was found in Alzheimer's tissues, possibly a consequence of bot h loss of neurogenic input and structural changes in blood vessel walls. The data indicate that intracortical microvessels and nitric oxide neurons in Alzheimer's disease are deprived of a cholinergic neurogenic control, a situation which is likely to result in a compromised ability to adapt corti cal perfusion to neuronal activation during functional tasks related to cog nition, arousal and attention. We conclude that such deficits in neurovascu lar regulation are likely to be an important pathogenic factor underlying c erebral blood flow dysfunctions in Alzheimer's disease. (C) 1999 IBRO. Publ ished by Elsevier Science Ltd.